Project Summary Approximately 30%-50% of individuals who come to autopsy without dementia have high levels of Alzheimer's disease (AD) pathology. Even in the AD population, the cellular feature most correlated with cognitive decline is not amyloid or tau, but synaptic density. However, the molecular mechanisms behind this synaptic loss are unclear. We have begun to explore their molecular basis through three dimensional (3D) modeling of dendritic spines. These results show that structural remodeling of spines not only relates to cognitive decline, but specifically relates to cognitive resilience to AD. Synaptic remodeling is highly plausible as the basis for cognitive resilience because it is the basis for short term memory and can affect multiple cognitive processes. This raises important questions: 1) what are the synaptic signaling pathways that drive structural remodeling of spines to maintain cognitive abilities in resilient individuals? 2) Can we identify therapeutic targets for drug repositioning or novel treatments to exploit these mechanisms in at risk patients? The goal of this proposal is to build a predictive model of cognitive resilience to AD by integrating quantitative proteomics, phospho- proteomics, 3D modeling of spines, and antemortem functional magnetic resonance imaging (fMRI) across two brain regions from the same individuals. From computational models, candidate therapeutic protein targets will be prioritized and rigorously validated in cellular and animal models of AD. Novel data acquired to support this goal will measure ~12,000 proteins and ~30,000 phosphorylation sites in synapse-rich fractions from human brains with varying degrees of resilience to AD pathology. In the same cases innovative high resolution imaging and 3D reconstruction of dendritic architecture will measure cellular phenotypes of resilience. Systems biology approaches will integrate our data with existing omics, including AMP-AD, and propose specific synaptic proteins that drive resilience. These predictions will be validated in terms of human brain structure and function by comparison to neuroimaging, acquired in the same set of humans. Top candidates for resilience will then be screened for resilience phenotypes in cellular and animal models of disease. Human clinical, radiologic, and pathologic data, from The Religious Orders Study and the Rush Memory and Aging Project will be studied in combination with AMP-AD data to complete the proposed goals.